JAK (Janus kinase) is a type of non-receptor tyrosine kinase family, in which there are 4 members found, which are JAK1, JAK2, JAK3 and TYK1, respectively. They do not comprise SH2 or SH3 in their structure, and there are two connected kinase areas in their C-terminal. The substrate of JAK is STAT, i.e., signaling transducers and activators of transcription. STAT is dimerizeted after being phosphorylated by JAK, and passes through nuclear membrane into nucleus to regulate the expression of relevant genes, which signal pathway is called JAK-STAT pathway, and plays a role in communication of hematopoietic cells and immune cells. Effective and specific inhibitors of the four JAK kinases currently known can be used to treat cancer, inflammation and other diseases. The selective JAK3 inhibitor, tofacitinib (product name: Xeljanz), of Pfizer is approved to be used for treating rheumatoid arthritis by the U.S. Food and Drug Administration in December of 2012.
Phenyl amino pyrimidine compounds and derivatives are a type of inhibitors of non-receptor tyrosine kinases such as JAK kinases. WO2008109943 and US2011212077 disclosed a series of phenyl amino pyrimidine derivatives in which the pyrimidine ring was 2,4-bis-substituted. Among these derivatives, the compound CYT387 is a selective JAK1 and JAK2 kinase inhibitor, with a chemical name of N-(cyanomethyl)-4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)benzamide, and is used in the treatment of cancer, myeloproliferative diseases and other related diseases. This compound is now under Phase II clinical trials of treating myeloproliferative diseases.
Although the targeted inhibition of different protein kinases is beneficial for the treatment of kinase-related diseases, the discovery of novel compounds which specifically inhibit certain protein kinases and have druggability such as excellent oral bioavailability is still found challenging. In addition, there are some side effects and drug resistance problems with some of the protein kinase inhibitors currently available on market.
Thus, there is still a need in the art to develop compounds having JAK kinase inhibitory activity or better pharmacodynamic properties.